{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T03:07:13Z","timestamp":1789268833476,"version":"build-2803163510"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T00:00:00Z","timestamp":1616112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Chronic inflammation is a common feature in many diseases of different organ systems, including bone. However, there are few interventions to mitigate chronic inflammation and preserve host tissue. Previous <jats:italic>in vitro<\/jats:italic> studies demonstrated that preconditioning of mesenchymal stem cells (pMSCs) using lipopolysaccharide and tumor necrosis factor-\u03b1 polarized macrophages from a pro-inflammatory to an anti-inflammatory phenotype and increased osteogenesis compared to unaltered MSCs. In the current study, we investigated the local injection of MSCs or pMSCs during the acute versus chronic inflammatory phase in a murine model of inflammation of bone: the continuous femoral intramedullary polyethylene particle infusion model. Chronic inflammation due to contaminated polyethylene particles decreased bone mineral density and increased osteoclast-like cells positively stained with leukocyte tartrate resistant acid phosphatase (TRAP) staining, and resulted in a sustained M1 pro-inflammatory macrophage phenotype and a decreased M2 anti-inflammatory phenotype. Local injection of MSCs or pMSCs during the chronic inflammatory phase reversed these findings. Conversely, immediate local injection of pMSCs during the acute inflammatory phase impaired bone healing, probably by mitigating the mandatory acute inflammatory reaction. These results suggest that the timing of interventions to facilitate bone healing by modulating inflammation is critical to the outcome. Interventions to facilitate bone healing by modulating acute inflammation should be prudently applied, as this phase of bone healing is temporally sensitive. Alternatively, local injection of MSCs or pMSCs during the chronic inflammatory phase may be a potential intervention to mitigate the adverse effects of contaminated particles on bone.<\/jats:p>","DOI":"10.3389\/fcell.2021.631063","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T04:43:56Z","timestamp":1616129036000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Different Effects of Intramedullary Injection of Mesenchymal Stem Cells During the Acute vs. Chronic Inflammatory Phase on Bone Healing in the Murine Continuous Polyethylene Particle Infusion Model"],"prefix":"10.3389","volume":"9","author":[{"given":"Takeshi","family":"Utsunomiya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzuhua","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Kohno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Maruyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Rhee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ejun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart B.","family":"Goodman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1002\/stem.1040","article-title":"Immune modulation with primed mesenchymal stem cells delivered via biodegradable scaffold to repair an Achilles tendon segmental defect.","volume":"35","author":"Aktas","year":"2017","journal-title":"J. Orthop. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1016\/j.ajpath.2019.02.006","article-title":"An overview of the derivation and function of multinucleated giant cells and their role in pathologic processes.","volume":"189","author":"Brooks","year":"2019","journal-title":"Am. J. Pathol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The International society for cellular therapy position statement.","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"B4","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1002\/jor.21548","article-title":"Selective inhibition of the MCP-1-CCR2 ligand-receptor axis decreases systemic trafficking of macrophages in the presence of UHMWPE particles.","volume":"30","author":"Gibon","year":"","journal-title":"J. Orthop. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3632","DOI":"10.1016\/j.biomaterials.2012.02.003","article-title":"Effect of a CCR1 receptor antagonist on systemic trafficking of MSCs and polyethylene particle-associated bone loss.","volume":"33","author":"Gibon","year":"","journal-title":"Biomaterials"},{"key":"B6","doi-asserted-by":"publisher","first-page":"5044","DOI":"10.1016\/j.biomaterials.2007.06.035","article-title":"Wear particles, periprosthetic osteolysis, and the immune system.","volume":"28","author":"Goodman","year":"2007","journal-title":"Biomaterials"},{"key":"B7","first-page":"201","article-title":"The basic science of perirosthetic osteolysis.","volume":"62","author":"Goodman","year":"2013","journal-title":"Instr. Course. Lect."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2013.0962","article-title":"Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement.","volume":"11","author":"Goodman","year":"2014","journal-title":"J. R. Soc. Interface"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2019.00230","article-title":"Inflammation and bone repair: from particle disease to tissue regeneration.","volume":"7","author":"Goodman","year":"2019","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"32378","DOI":"10.1074\/jbc.M110.136895","article-title":"Bacterial pathogen-associated molecular patterns stimulate biological activity of orthopaedic wear particles by activating cognate Toll-like receptors.","volume":"285","author":"Greenfield","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B11","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1002\/stem.1040","article-title":"Induction of osteogenesis in mesenchymal stem cells by activated monocytes\/macrophages depends on oncostatin M signaling.","volume":"30","author":"Guihard","year":"2012","journal-title":"Stem. Cells"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2019.00268","article-title":"Adult stem cells for bone regeneration and repair.","volume":"12","author":"Iaquinta","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"624","DOI":"10.2106\/JBJS.M.00285","article-title":"Impact of the economic downturn on total joint replacement demand in the United States: updated projections to 2021.","volume":"96","author":"Kurtz","year":"2014","journal-title":"J. Bone. Joint. Surg. Am."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1089\/ten.TEA.2018.0292","article-title":"Preconditioned or IL4-Secreting mesenchymal stem cells enhanced osteogenesis at different stages.","volume":"25","author":"Lin","year":"2019","journal-title":"Tissue. Eng. Part. A"},{"key":"B15","doi-asserted-by":"publisher","first-page":"2744","DOI":"10.1002\/jbm.a.36504","article-title":"NF\u03baB sensing IL-4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles.","volume":"106","author":"Lin","year":"2018","journal-title":"J. Biomed. Mater. Res. A"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-017-0730-z","article-title":"Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis.","volume":"8","author":"Lin","year":"2017","journal-title":"Stem. Cell. Res. Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.actbio.2016.05.038","article-title":"NF-\u03baB decoy oligodeoxynucleotide mitigates wear particle-associated bone loss in the murine continuous infusion model.","volume":"41","author":"Lin","year":"2016","journal-title":"Acta. Biomater."},{"key":"B18","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.bone.2016.02.020","article-title":"Inflammation, fracture and bone repair.","volume":"86","author":"Loi","year":"","journal-title":"Bone"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-016-0276-5","article-title":"The effects of immunomodulation by macrophage subsets on osteogenesis in vitro.","volume":"7","author":"Loi","year":"","journal-title":"Stem. Cell. Res. Ther"},{"key":"B20","doi-asserted-by":"crossref","first-page":"3728","DOI":"10.1016\/j.biomaterials.2008.05.031","article-title":"An in vivo murine model of continuous intramedullary infusion of polyethylene particles.","volume":"29","author":"Ma","year":"2008","journal-title":"Biomaterials"},{"key":"B21","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1089\/ten.TEB.2017.0242","article-title":"Multinucleated giant cells: good guys or bad guys?","volume":"24","author":"Miron","year":"2018","journal-title":"Tissue. Eng. Part B Rev."},{"key":"B22","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.actbio.2016.09.029","article-title":"Giant cells around bone biomaterials: osteoclasts or multi-nucleated giant cells?","volume":"46","author":"Miron","year":"2016","journal-title":"Acta Biomater."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.biomaterials.2016.11.039","article-title":"Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model.","volume":"117","author":"Nabeshima","year":"2017","journal-title":"Biomaterials"},{"key":"B24","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.biomaterials.2017.12.025","article-title":"Mesenchymal stem cell-macrophage crosstalk and bone healing.","volume":"196","author":"Pajarinen","year":"2019","journal-title":"Biomaterials"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1089\/ten.TEC.2017.0166","article-title":"Murine model of progressive orthopedic wear particle-induced chronic inflammation and osteolysis.","volume":"23","author":"Pajarinen","year":"2017","journal-title":"Tissue Eng. Part C Methods"},{"key":"B26","doi-asserted-by":"publisher","first-page":"3147","DOI":"10.1039\/d0bm00147c","article-title":"ZBTB20-mediated titanium particle-induced peri-implant osteolysis by promoting macrophage inflammatory responses.","volume":"8","author":"Qiu","year":"2020","journal-title":"Biomater. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/s11999-010-1645-5","article-title":"Continuous infusion of UHMWPE particles induces increased bone macrophages and osteolysis.","volume":"469","author":"Ren","year":"2011","journal-title":"Clin. Orthop. Relat. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1002\/jbm.a.35759","article-title":"The effect of local IL-4 delivery or CCL2 blockade on implant fixation and bone structural properties in a mouse model of wear particle induced osteolysis.","volume":"104","author":"Sato","year":"2016","journal-title":"J. Biomed. Mater. Res. A"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3872","DOI":"10.1002\/jbm.a.35532","article-title":"NF-\u03baB decoy oligodeoxynucleotide inhibits wear particle-induced inflammation in a murine calvarial model.","volume":"103","author":"Sato","year":"2015","journal-title":"J. Biomed. Mater. Res. A"},{"key":"B30","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1007\/s12015-015-9633-5","article-title":"Primed mesenchymal stem cells alter and improve rat medial collateral ligament healing.","volume":"12","author":"Seather","year":"2016","journal-title":"Stem. Cell. Rev."},{"key":"B31","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1038\/cr.2010.44","article-title":"Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair.","volume":"20","author":"Shi","year":"2010","journal-title":"Cell. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1002\/jbm.a.36982","article-title":"IL-4 overexpressing mesenchymal stem cells within gelatin-based microribbon hydrogels enhance bone healing in a murine long bone critical-size defect model.","volume":"108","author":"Ueno","year":"2020","journal-title":"J. Biomed. Mater. Res. A"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.631063\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T04:44:02Z","timestamp":1616129042000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.631063\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,19]]},"references-count":32,"alternative-id":["10.3389\/fcell.2021.631063"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.631063","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,19]]},"article-number":"631063"}}